PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas

Nat Med. 2012 Nov;18(11):1699-704. doi: 10.1038/nm.2966. Epub 2012 Oct 14.

Abstract

Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anaplastic Lymphoma Kinase
  • Animals
  • Benzamides
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imatinib Mesylate
  • Lymphoma, Large-Cell, Anaplastic* / drug therapy
  • Lymphoma, Large-Cell, Anaplastic* / metabolism
  • Lymphoma, Large-Cell, Anaplastic* / pathology
  • Mice
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Neoplasm Staging
  • Nuclear Proteins* / genetics
  • Nuclear Proteins* / metabolism
  • Oncogene Protein p65(gag-jun) / genetics
  • Oncogene Protein p65(gag-jun) / metabolism
  • Piperazines / administration & dosage
  • Protein-Tyrosine Kinases* / genetics
  • Protein-Tyrosine Kinases* / metabolism
  • Pyrimidines / administration & dosage
  • Receptor Protein-Tyrosine Kinases* / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases* / genetics
  • Receptor Protein-Tyrosine Kinases* / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha* / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor alpha* / genetics
  • Receptor, Platelet-Derived Growth Factor alpha* / metabolism
  • Receptor, Platelet-Derived Growth Factor beta* / antagonists & inhibitors
  • Receptor, Platelet-Derived Growth Factor beta* / genetics
  • Receptor, Platelet-Derived Growth Factor beta* / metabolism
  • Remission Induction
  • Stem Cell Transplantation
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Translocation, Genetic

Substances

  • Benzamides
  • Nuclear Proteins
  • Oncogene Protein p65(gag-jun)
  • Piperazines
  • Pyrimidines
  • Transcription Factor AP-1
  • nucleophosmin
  • Imatinib Mesylate
  • p80(NPM-ALK) protein
  • ALK protein, human
  • Alk protein, mouse
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptor, Platelet-Derived Growth Factor beta